Chronic lymphocytic leukemia (CLL) is the most prevalent adult leukemia in the U.S., and there is an increased incidence among relatives of affected patients (familial CLL). Although the etiology of CLL is unknown, several recurrent cytogenetic abnormalities have been described. Recent reports suggest low numbers of CLL-phenotype cells can be detected in 3.5% of healthy adults by flow cytometry, with a striking 4-fold greater frequency in relatives of patients with familial CLL, a detection rate of 13.5%. Because little is known about these cells, the term "clonal lymphocytosis of unknown significance" (CLUS) has been applied. We hypothesize that development of familial CLL is a stepwise process that includes an initial, inherited abnormality that increases chromosomal instablility in B lymphocytes. This may lead to additional mutations in genes that contribute to the accumulation of these abnormal cells, manifested initially by CLUS. Subsequent events may then lead to the development of clinical CLL. To begin to study this process, we will utilize the Utah Population Database to identify CLL families, and a Utah Familial CLL Registry will be established. This will include participants known to have CLL and unaffected relatives. Since the nature of the underlying predisposing genetic abnormality may be reflected in clinical characteristics of these familial CLL cases, we will analyze clinical, immunophenotypic and molecular factors to comprehensively characterize familial CLL and carefully compare to sporadic CLL Furthermore, the peripheral blood lymphocytes of the unaffected members will be analyzed for CLUS cells to determine the prevalence of CLUS in the Utah families. These CLUS cells will be isolated for biological and molecular studies including antigen expression important for CLL prognosis, such as CD 38 and ZAP-70, and assessment of chromosomal abnormalities detectable by fluorescence in situ hybridization. Finally, the structure and phenotypic characteristics of these families will allow for simulation of linkage analysis strategies for planned investigation of the underlying gene(s) responsible for this predisposition. Ultimately, we anticipate that this insight into the multi-step pathway leading to CLL will lead to better detection and prediction of risk of development of CLL, possible early intervention to change the natural history of the disease, and identification of new therapeutic targets.